Protein degradation in signaling

Recent studies have linked proteolysis by the ubiquitin/proteasome pathway to a variety of signaling pathways in higher plants. These links were uncovered by characterization of mutants altered in signaling or by targeted disruption of components of the proteolytic pathway. Significant advances have recently revealed connections between proteolysis and hormone responses, light perception, environmental adaptation, and floral development.     

Protein kinase signaling networks in cancer

Protein kinases orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation, and survival. The complexity of numerous intracellular signaling pathways is highlighted by the number of kinases encoded by the human genome (539) and the plethora of phosphorylation sites identified in phosphoproteomic studies. Perturbation of these signaling networks by mutations or abnormal protein expression underlies the cause of many diseases including cancer. Recent RNAi screens and cancer genomic sequencing studies have revealed that many more kinases than anticipated contribute to tumorigenesis and are potential targets for inhibitor drug development intervention. This review will highlight recent insights into known pathways essential for tumorigenesis and discuss exciting new pathways for therapeutic intervention.     

Protein misfolding, aggregation, and degradation in disease

Pathologies associated with protein misfolding have been observed in neurodegenerative diseases such as Alzheimer’s disease, metabolic diseases like phenylketonuria, and diseases affecting structural proteins like collagen or keratin. Misfolding of mutant proteins in these and many other diseases may result in premature degradation, formation of toxic aggregates, or incorporation of toxic conformations into structures. We review common traits of these diverse diseases under the unifying view of protein misfolding. The molecular pathogenesis is discussed in the context of protein quality control systems consisting of molecular chaperones and intracellular proteases that assist the folding and supervise the maintenance of the folded structure. Furthermore, genetic and environmental factors that may modify the severity of these diseases are underscored. The present article represents a partly revised and updated version of chapter 1 published earlier in volume 232 of the series Methods in Molecular Biology (Walker, J. M., ed., Humana Press, Totowa, NJ), Protein Misfolding and Disease: Principles and Protocols (Bross, P. & Gregersen, N., eds.), pp. 3–16 (2003).     

The role of microRNAs involved in PI3-kinase signaling pathway in colorectal cancer

In recent decades, cancer has been one of the most important concerns of the human community, which affects human life from many different ways, such as breast, lung, colorectal, prostate, and other cancers. Colorectal cancer is one of the most commonly diagnosed cancers in the world that has recently been introduced as the third leading cause of cancer deaths in the world. microRNAs have a very crucial role in tumorgenesis and prevention of cancer, which plays a significant role with influencing various factors through different signaling pathways. Phosphoinositide 3 (PI3)-kinase/AKT is one of the most important signaling pathways involved in the control and growth of tumor in colorectal cancer, through important proteins of this pathway, such as PTEN and AKT, that they can perform specific influence on this process. Our effort in this study is to collect microRNAs that act as tumor suppressors and oncomirs in this cancer through PI3-kinase/AKT signaling pathway.     

let-7 microRNAs in development, stem cells and cancer

MicroRNAs (miRNAs) are small noncoding RNAs, approximately 22 nucleotides in length, that repress target messenger RNAs (mRNAs) through an antisense mechanism. The let-7 miRNA was originally discovered in the nematode Caenorhabditis elegans, where it regulates cell proliferation and differentiation, but subsequent work has shown that both its sequence and its function are highly conserved in mammals. Recent results have now linked decreased let-7 expression to increased tumorigenicity and poor patient prognosis. Moreover, during normal development, accumulation of let-7 can be prevented by LIN28, a promoter of pluripotency. Based on these findings, we propose that let-7 regulates 'stemness' by repressing self-renewal and promoting differentiation in both normal development and cancer. A more complete understanding of its function will thus provide insights into these processes and might yield diagnostic and therapeutic advances for cancer treatment.     

Protein kinase C, calcium and phospholipid degradation.

In most cells, calcium signals are transient, while the resulting physiological responses often persist longer. The sustained activation of protein kinase C has been postulated to be essential for maintaining such cellular responses. It is becoming clear that an elaborate network involving protein kinase C, calcium and degradation of membrane phospholipids may generate several molecules that are necessary for sustaining the activation of protein kinase C itself. Multiple members of the protein kinase C family show distinct responses to calcium and the phospholipid degradation products, suggesting their unique functions in cell signalling.     

Catenins, Wnt signaling and cancer

Recent studies indicate that plakoglobin may have a similar function to that of beta-catenin within the Wnt signaling pathway. beta-catenin is known to be an oncogene in many forms of human cancer, following acquisition of stabilizing mutations in amino terminal sequences. Kolligs(1) and coworkers show, however, that unlike beta-catenin, plakoglobin induces neoplastic transformation of rat epithelial cells in the absence of such stabilizing mutations. Cellular transformation by plakoglobin also appears to be distinct from that of beta-catenin in that it requires activation of the proto-oncogene c-myc. Surprisingly, c-myc is activated more efficiently by plakoglobin than beta-catenin, despite its previous identification as a target of Tcf/beta-catenin.(2) In contrast, a synthetic Tcf reporter gene is activated to a much greater extent by beta-catenin than plakoglobin. Plakoglobin and beta-catenin may therefore have different roles in Wnt signaling and cancer, which reflect their differential effects on target gene activity.     

Protein degradation and iron homeostasis

Regulation of both systemic and cellular iron homeostasis requires the capacity to sense iron levels and appropriately modify the expression of iron metabolism genes. These responses are coordinated through the efforts of several key regulatory factors including F-box and Leucine-rich Repeat Protein 5 (FBXL5), Iron Regulatory Proteins (IRPs), Hypoxia Inducible Factor (HIF), and ferroportin. Notably, the stability of each of these proteins is regulated in response to iron. Recent discoveries have greatly advanced our understanding of the molecular mechanisms governing iron-sensing and protein degradation within these pathways. It has become clear that iron's privileged roles in both enzyme catalysis and protein structure contribute to its regulation of protein stability. Moreover, these multiple pathways intersect with one another in larger regulatory networks to maintain iron homeostasis. This article is part of a Special Issue entitled: Cell Biology of Metals.     

The garden of forking paths: recycling, signaling, and degradation

Three recent papers in Developmental Cell (by Yamamoto et al., Choi et al., and Sigismund et al.) show that the endocytic route of internalization can determine whether signaling receptors are degraded or recycled, and whether they initiate signaling from an endosomal platform. However, the same route can serve opposite functions in different signaling pathways: there is no "unifying theory" of trafficking.     

BRCA1, microRNAs and cancer predisposition: Challenging the dogma

Comment on: Pelletier C, et al. Cell Cycle 2011; 10:90–1

     

microRNAs: New prognostic,diagnostic, and therapeutic biomarkers in cervical cancer

Cervical cancer is as a kind of cancer beginning from the cervix. Given that cervical cancer could be observed in women who infected with papillomavirus, regular oral contraceptives, and multiple pregnancies. Early detection of cervical cancer is one of the most important aspects of the therapy of this malignancy. Despite several efforts, finding and developing new biomarkers for cervical cancer diagnosis are required. Among various prognostic, diagnostic, and therapeutic biomarkers, miRNA have been emerged as powerful biomarkers for detection, treatment, and monitoring of response to therapy in cervical cancer. Here, we summarized various miRNAs as an employable platform for prognostic, diagnostic, and therapeutic biomarkers in the treatment of cervical cancer.     

Protein degradation in mitochondria

The biogenesis of mitochondria and the maintenance of mitochondrial functions depends on an autonomous proteolytic system in the organelle which is highly conserved throughout evolution. Components of this system include processing peptidases and ATP-dependent proteases, as well as molecular chaperone proteins and protein complexes with apparently regulatory functions. While processing peptidases mediate maturation of nuclear-encoded mitochondrial preproteins, quality control within various subcompartments of mitochondria is ensured by ATP-dependent proteases which selectively remove non-assembled or misfolded polypeptides. Moreover; these proteases appear to control the activity- or steady-state levels of specific regulatory proteins and thereby ensure mitochondrial genome integrity, gene expression and protein assembly.     

The role of microRNAs in prostate cancer migration,invasion, and metastasis

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.